HIV-infected persons are at greater risk of accelerated aging complications, including premature kidney, heart, and bone diseases. In the presence of HIV infection, the effect of aging on the kidney appears to be accelerated by 1-2 decades. HIV-infected persons have a 10-fold prevalence of impaired kidney function and risk of end-stage renal disease (ESRD) compared with matched controls. In addition, kidney disease adversely affects bone health and is associated with fracture risk. These effects may be compounded by the nephrotoxic effects of tenofovir, a first-line treatment of HIV infection, which has been associated with decreased bone mineral density; tenofovir's bone toxicity is likely due to kidney tubular injury and resulting impairments in bone mineral homeostasis. It is widely agreed that the key strategy to prevent the complications of kidney disease is early diagnosis and provision of care. However, a major challenge in clinical practice is the current reliance on serum creatinine and albuminuria testing to detect kidney injury and disease. Kidney function estimates based on creatinine are unreliable until the glomerular filtration rate (GFR) has been substantially reduced; by this time, kidney disease is established and the primary prevention window has closed. Albuminuria captures only a small fraction of the kidney injury in HIV-infected persons and is therefore insufficient as a screening tool for kidney disease. This proposal envisions a new paradigm for early diagnosis of kidney disease in persons with HIV-infection. The strategy will be to use targeted serum and urine biomarkers to detect kidney injury at its earliest stages at multiple sites within the kidney, and to determine whether early kidney injury adversely effects bone mineral metabolism in ways that lead to accelerated osteoporosis. To address these key issues related to kidney disease in the aging HIV-infected population, we will add novel biomarkers of injury to the microvasculature, tubules, and interstitium of the kidney and of bone mineral metabolism to the ongoing Multicenter AIDS Cohort Study (MACS) and the Women's Interagency HIV Study (WIHS). Our first objective will be to compare kidney injury markers among HIV-infected and uninfected participants cross-sectionally, and their association with age, tenofovir use, and GFR. The second objective will be to examine the link between HIV-infection, advancing age, declining GFR, and tenofovir use with the disorders of mineral metabolism and reduced bone mineral density. The third objective will be to evaluate longitudinally whether baseline and follow-up markers of kidney injury are independently associated with accelerated declines in kidney function during follow-up. PUBLIC HEALTH RELEVANCE: Age-related declines in kidney function appear to be accelerated by nearly two decades in HIV-infected persons, and the resulting kidney disease predisposes to higher risk of death and bone disease. Current strategies for detecting kidney disease are narrowly focused, providing a diagnosis in only a small fraction of affected individuals or diagnosing the disease late in its course. This proposal envisions a new paradigm for early detection of kidney injury in persons with HIV-infection through the use of novel, site-specific serum and urine biomarkers to detect injury at multiple locations within the kidney at their earliest, preclinical stage.